Rivaroxaban is an orally active factor Xa inhibitor developed by Bayer Healthcare for the prevention and treatment of deep vein thrombosis and pulmonary embolism in patients undergoing knee and hip replacement surgery. Rivaroxaban has an oxazolidinone nucleus and chemically is known as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide, represented by the following structural formula:
Currently, Rivaroxaban is marketed under trade name XARELTO® by Janssen Pharmaceuticals, Inc.
Rivaroxaban was first disclosed in U.S. Pat. No. 7,157,456 (herein, “the '456 patent”), where it is prepared by reacting 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (X) with 4-(4-aminophenyl)-3-morpholinone (II) to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-1H-isoindole-1,3(2H)-dione (XI), as depicted in Scheme 1. The obtained compound is cyclized in the presence of dimethylaminopyridine, tetrahydrofuran and N,N′-carbonyldiimidazole to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (XII). Elimination of the phthalimide protective group affords compound (XIII), which is used, without further purification, in the last step of the synthetic route. Crude Rivaroxaban (I) is obtained by adding 5-chlorothiphene-2-carbonylchloride (VIII) to a solution of the compound XIII in pyridine. Purification of Rivaroxaban is carried out by means of flash chromatography.
The process of the '456 patent has several disadvantages, such as low yield, usage of expensive starting materials, and unwanted side reactions. The side reactions result in a final product of low purity, making chromatographic purification methods unavoidable and not feasible at an industrial scale. Additionally, the process involves the use of pyridine, which is a well known carcinogen, as a solvent and base.

U.S. Pat. No. 8,106,192 (herein, “the '192 patent”) describes another process for preparation of Rivaroxaban as shown in scheme II. In the process of the '192 patent, 5-chlorothiophene-2-carbonyl chloride (VIIIa) is reacted with (2S)-3-aminopropane-1,2-diol hydrochloride (XIV) to yield 5-chlorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide (XV), which is further brominated using a solution of 33% hydrobromic acid in acetic acid. The resulting bromo compound (XVI) is condensed with 4-(4-aminophenyl)-3-morpholinone (II) to yield N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl amino]propyl}-5-chloro-thiophene-2-carboxamide (XVII), which is further cyclized to obtain Rivaroxaban (I) in the presence of 1-methyl-2-pyrrolidone and N,N-carbonyldiimidazole.

The process disclosed in the '192 patent involves the use of hazardous reagents, such as hydrobromic acid and N-methyl-2-pyrrolidone. N-methyl-2-pyrrolidone is known to be an irritant to skin and eyes and has also been identified as a reproductive toxicant. Thus, the process of the '192 patent is not feasible on an industrial scale.
Another process for the preparation of Rivaroxaban is described in U.S. Pat. No. 7,816,355 (herein, “the '355 patent”), as depicted in scheme III. The process involves the use of methyl N-(2R,3-epoxy-1-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (XX) as an intermediate for the synthesis of Rivaroxaban (I). This intermediate can be synthesized by reacting 4-(4-amino-phenyl)-morpholin-3-one (II) with (R)-(−)epichlorohydrine (III) to yield 4-[4-(N-(2R,3-epoxy-1-propyl)amino)phenyl]morpholin-3-one (XIX), which is further reacted with methyl chloroformate to provide said intermediate. Alternatively, this intermediate can be prepared by reacting 4-(4-amino-phenyl)-morpholin-3-one (II) with methyl chloroformate to give methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (XVIII), which, on further reaction with (R)-(−)epichlorohydrine (III), provides said intermediate. The final step of the synthetic route involves condensation of this carbamate (XX) intermediate with 5-chlorothiophene-2-carboxamide (XXI) to yield Rivaroxaban (I).

The process disclosed in the '355 patent employs haloformates intermittently which are hazardous, corrosive and difficult to handle on an industrial scale.
In view of the above disadvantages of the prior art processes, there is a need to develop an improved process for the preparation of Rivaroxaban, which is industrially feasible and can avoid the use of potentially hazardous and expensive chemicals. Moreover, an improved process should avoid formation of isomeric and other process related impurities, while providing the desired product in high yield and purity.